Project Summary To date, endothelial dysfunction is defined by a constellation of phenotypes including up-regulation of pro-inflammatory pathways, enhanced thrombogenicity, increased reactive oxygen species and reduced NO synthesis/bioavailability1, 2. Our lab has focused on the latter pathway by understanding how endothelial nitric oxide synthase (eNOS), the exclusive source of endothelial derived NO as a relaxing factor for smooth muscle, is regulated and these studies have led to the discovery of additional pathways that regulate several aspects of endothelial cell biology and function3. Thus, the central goal for this grant is to integrate advances derived from our previous work on eNOS to explore a broader range of pathways that can improve endothelial and vascular health.